Cardiovascular disease is a major cause of morbidity and mortality in African-Americans, yet remarkably few mechanistic studies have focussed on this group. We hypothesize that there is enhanced, autonomically-mediated vascular tone in African-Americans; this enhanced tone may play an important role in the pathogenesis of cardiovascular disease. Evidence for interethnic differences includes the demonstration of enhanced pressor responses to psychological stressors, increased sympathetic activity after cold pressor testing, an increased frequency of salt sensitivity, and more recently, our observations 1) that forearm vascular responses to the beta- adrenergic agonist, isoproterenol are attenuated in normotensive African- Americans and 2) that ethnicity and gender both influence the psychological traits associated with adverse cardiovascular outcomes. This project will define the mechanisms for the interethnic differences in the regulation of vascular tone through two specific aims. Our strategy will be (Specific Aim l) to utilize pharmacologic probes, with different receptor and non-receptor modes of action, to localize the sites responsible for the interethnic difference in vasodilation. Thus, the known interethnic differences in cardiovascular responses to stress may reflect differences in autonomic control at multiple levels and based on our preliminary data, we propose that differences in psychological traits may predict autonomically-mediated cardiovascular responses. We will determine (Specific Aim 2) the mechanism(s) of interethnic differences in autonomic reactivity by specifically probing central and peripheral levels of autonomic control, using directly measured muscle sympathetic nerve activity (MSNA) and norepinephrine kinetics to examine interethnic differences in basal awake and asleep sympathetiC activity, in stimulated (physiologic, pharmacologic, psychologic, nociceptive) and inhibited (pharmacologic and baroreflex) sympathetic activity, and in presynaptic receptor sensitivity. By defining the factors contributing to the altered cardiovascular response in African-Americans, physicians will be better able to tailor therapy to this group and reduce their present excessive burden of cardiovascular disease.